The road was paved west of East Petersburg by 1911 and east of there by 1926. PA 722 was designated by 1930 between U.S. Route 230 (US 230) in Bamford and US 222 and PA 772 in Brownstown. The eastern terminus was moved to its current location at US 222 (now PA 272) in the 1930s, with US 222 replacing the route east of there. The western terminus was moved to its current location following a realignment of US 230 in 1949. The western terminus was upgraded to an interchange in 1969 as part of improving PA 230 (which replaced US 230, now PA 283) to a freeway.

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PA 722 begins at an interchange with the PA 283 freeway in East Hempfield Township, Lancaster County, heading north on two-lane undivided State Road. South of this interchange, State Road continues as a local road. From PA 283, the route passes a couple businesses before heading into agricultural areas, turning to the east. The road crosses Norfolk Southern's Lititz Secondary and enters the borough of East Petersburg, where the name becomes State Street. PA 722 heads northeast through residential areas with some businesses, curving to the east and intersecting the western terminus of PA 741. A block later, the route crosses PA 72 in the center of East Petersburg. The road continues past homes and becomes Cottage Avenue, curving to the north and then to the northeast. PA 722 crosses the Little Conestoga Creek into Manheim Township and becomes Petersburg Road, winding east through suburban residential areas with some businesses. The route heads through Groffs Corner and passes to the south of a farm before turning southeast past more homes and reaching a junction with PA 501 in Neffsville.[2][3]

At this point, PA 722 turns north to form a concurrency with PA 501 on Lititz Pike, passing through suburban development. PA 722 splits from PA 501 by heading east along East Oregon Road, passing through suburban neighborhoods. The road turns north and heads into industrial areas, where it bends east. The route continues through agricultural areas with a couple residential subdivisions to the south of the road. Farther east, PA 722 passes through the residential community of Oregon and crosses Lititz Run before it reaches its eastern terminus at an intersection with PA 272.[2][3]

When Pennsylvania first legislated routes in 1911, present-day PA 722 was not given a route number. At this time, the road was paved west of East Petersburg while the road between East Petersburg and Oregon was unpaved.[4] By 1926, the road between East Petersburg and Oregon was paved.[5] PA 722 was designated by 1930 to run from US 230 (Harrisburg Pike) in Bamford east to US 222 and the eastern terminus of PA 772 in Brownstown, heading north on State Road, east on its current alignment to Oregon, and northeast on Oregon Pike.[6] In the 1930s, the eastern terminus of the route was cut back to US 222 (now PA 272) in Oregon, with US 222 replacing the route between Oregon and Brownstown.[7] The western terminus of PA 722 was cut back to a realigned US 230 in 1949.[8][9] In 1969, the intersection with PA 230 (which replaced US 230, now PA 283) was upgraded to an interchange as part of converting PA 230 to a freeway.[10][11]